Impaired insulin-mediated amino acid plasma disappearance in non-alcoholic fatty liver disease: a feature of insulin resistance

Bianchi, Giampaolo; Marchesini, Giulio; Brunetti, Nicoletta; Manicardi, Elisa; Montuschi, F.; Chianese, R.; Zoli, Marco

doi:10.1016/s1590-8658(03)00416-x

Cited by 20 publications

(16 citation statements)

References 27 publications

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“…(10) In subjects with NAFLD, impaired suppression of BCAAs during hyperinsulinemic euglycemic clamp was proportional to impaired muscle glucose uptake during the clamp and peripheral IR. (12) Women with abdominal obesity, but not those with lower obesity, showed impaired suppression of leucine during the hyperinsulinemic euglycemic clamp procedure. (36) Thus, it is not clear if subjects with NAFLD have an altered hepatic metabolism of AAs or if AAs are increased because of obesity and IR, given that the majority of patients with NAFLD also have obesity.…”

Section: Impact Of Insulin Resistance On Plasma Amino Acid Concentrationmentioning

confidence: 90%

“…BCAAs and AAAs were also correlated with liver enzymes ALT (BCAAs, R 5 0.48, P < 0.0001; AAAs, R 5 0.37, P < 0.004), AST (BCAAs, R 5 0.25, P 5 0.04; AAAs, R 5 0.22 P 5 0.07), and GGT (BCAAs, R 5 0.42, P 5 0.0008; AAAs, R 5 0.31 P 5 0.01) (data not shown). Bianchi et al (12) 39 biopsy-proven NAFLD and 10 control subjects Reduced serine and glycine in NAFLD. Greater suppression of BCAA and serine during insulin clamp, associated with higher M value Newgard et al (8) 74 obese and 67 lean subjects with insulin resistance Increased BCAA, tyrosine, phenylalanine, alanine, glutamate/ glutamine, and decreased glycine in obese subjects Kalhan et al (6) Nondiabetic subjects with hepatic steatosis (n 5 11) or NASH (n 5 24) compared to healthy controls (n 5 25).…”

Section: Clinical Characteristics Of the Study Subjectsmentioning

confidence: 99%

“…(8)(9)(10) However, some researchers question if AAs are really causally linked to T2DM and other metabolic diseases or if increased concentrations of AAs are due to prevailing IR or possibly impaired tissue metabolism. (9,11,12) Fasting plasma levels of BCAAs (i.e., leucine, isoleucine, and valine) are often found increased and associated with peripheral IR. (6,8) Plasma concentrations of aromatic AAs (AAAs, e.g., tyrosine and phenylalanine) were also found increased with increased severity of liver diseases.…”

mentioning

confidence: 99%

“…Studies in animals (e.g., Sunny et al (15) ) have also been inconclusive because they compare age-matched animals treated with a high-fat diet (versus chow diet) without accounting for the increase in IR. In addition to BCAAs and AAAs, other AAs, such as glutamate, glutamine, alanine, and aspartate, have been found to be positively associated with increased cardiometabolic risk and particularly with Hep-IR, (12,(17)(18)(19) while glycine and serine were found decreased in metabolic diseases, including NAFLD. (19)(20)(21)(22)(23) Thus, the first aim of our study was to evaluate if plasma AA concentrations were increased/decreased similarly in subjects with and without obesity but with NAFLD and their association with the degree of fasting Hep-IR and peripheral IR.…”

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confidence: 99%

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Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

et al. 2017

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Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR 5 endogenous glucose production 3 insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine 1 glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R 5 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (HEPATOLOGY 2018;67:145-158).

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Section: Impact Of Insulin Resistance On Plasma Amino Acid Concentrationmentioning

confidence: 90%

Section: Clinical Characteristics Of the Study Subjectsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

et al. 2017

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“…Thus, the unraveling of the myriad connections between nutrients and alcohol and their metabolic and disease implications continues to challenge our critical thinking. Though the main risk factors for NAFLD are the metabolic abnormalities commonly observed in metabolic syndrome, such as insulin resistance, visceral obesity, dyslipidemia and altered adipokine profile (28); insulin resistance affects amino acid metabolism (29). However, the contribution of other factors of NAFLD on amino acid metabolism is not known.…”

Section: Amino Acids In Liver Diseasesmentioning

confidence: 99%

Role of plasma amino acids and gaba in alcoholic and non-alcoholic fatty liver disease-a pilot study

Mukherjee

Vaidyanathan

Vasudevan

et al. 2010

Indian J Clin Biochem

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Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high‐resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography–mass spectrometry was performed on plasma samples from a combined cross‐sectional sample of children and adolescents ages 2‐25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole‐body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

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Impaired insulin-mediated amino acid plasma disappearance in non-alcoholic fatty liver disease: a feature of insulin resistance

Cited by 20 publications

References 27 publications

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

Role of plasma amino acids and gaba in alcoholic and non-alcoholic fatty liver disease-a pilot study

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics

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